Cathepsin S is a member of the papain superfamily of cysteine proteases which also encompasses Cathepsins B, H, L, O and K. Cathepsin S plays a key role in the processing of invariant chain in MHC class II complexes allowing the complex to associate with antigenic peptides. MHC class II complexes are then transported to the surface of the cell for presentation to effector cells such as T cells. The process of antigen presentation is a fundamental step in initiation of the immune response. In this respect inhibitors of cathepsin S could be useful agents in the treatment of inflammation and immune disorders such as, but not limited to, asthma, rheumatoid arthritis, multiple sclerosis and Crohn's disease. Cathepsin S has also been implicated in a variety of other diseases involving extracellular proteolysis such as the development of emphysema in COPD through degradation of elastin and in Alzheimers disease.
Other Cathepsins notably K and L have been shown to degrade bone collagen and other bone matrix proteins. Inhibitors of these cysteine proteases would be expected to be useful in the treatment of diseases involving bone resorption such as osteoporosis.
The present invention therefore provides use of a compound of formula (I)
in which:    X is N or CA where A is hydrogen, halogen, CHR2R3, OR2, NR2R3, SR2;    R2 and R3 are independently hydrogen, C1-6 alkyl or C3-6 cycloalkyl both of which can optionally contain one or more O, S or NR4 groups where R4 is hydrogen or C1-6 alkyl, and can be optionally substituted by aryl, heteroaryl, NR5R6 where R5 and R6 together with the nitrogen atom to which they are attached form a 4–7 membered ring optionally containing a further O, S, NR4, or R2 and R3 together with the nitrogen atom to which they are attached form a 4–7 membered ring optionally containing a further O, S, NR4 group, or R2 and R3 are aryl or heteroaryl groups, both aryl and heteroaryl groups being optionally substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR7R8, SO2NR7R8, SO2R4, trifluoromethyl, NHSO2R4, NHCOR4, ethylenedioxy, methylenedioxy, C1-6 alkyl, C1-6 alkoxy, NR7R8 or SR7 where R7 and R8 are independently hydrogen or C1-6 alkyl;    R and R1 are independently a group Y(CH2)pR9 where p is 0, 1, 2 or 3 and Y is O or NR10 where R10 is hydrogen, C1-6 alkyl or C3-6 cycloalkyl;    and R9 is hydrogen, C1-6 alkyl which can optionally contain one or more O, S or NR4 groups where R4 is hydrogen or C1-6 alkyl, or a 3 to 7-membered saturated ring optionally containing a carbonyl group, one or more O, S or N atoms, or an aryl or heteroaryl group containing one to four heteroatoms selected from O, S or N, the saturated ring, aryl and heteroaryl groups all being optionally substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR7R8, SO2NR7R8, SO2R4, trifluoromethyl, NHSO2R4, NHCOR4, ethylenedioxy, methylenedioxy, C1-6 alkyl, C1-6 alkoxy, SR5 or NR11R12 where R11 and R12 are independently hydrogen, C1-6 alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR4 group;    or R/R1 is a group NR10(CHR10)CONR2R3 or NR10(CH2)qCONR2R3 where q is 1, 2 or 3;    or R/R1 is a group NR13R14 where R13 and R14 together with the nitrogen atom to which they are attached form a 4 to 7-membered saturated ring optionally containing a carbonyl group, O, S or N atom and optionally substituted by C1-6 alkyl, amino, hydroxy, CO2C1-6 alkyl, halogen, NR5R6, NR7R8, C1-6 alkylNR17R18 where R17 and R18 are independently hydrogen or C1-6 alkyl, CONR15R16 where R15 and R16 are independently hydrogen or C1-6alkyl, or optionally substituted by aryl, phenoxy, COphenyl, or a heteroaryl group, the latter four groups being optionally substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR7R8, SO2NR7R8, SO2R4, trifluoromethyl, NHSO2R4, NHCOR4, ethylenedioxy, methylenedioxy, C1-6 alkyl, C1-6 alkoxy, SR5 or NR11R12 where R11 and R12 are independently hydrogen, C1-6 alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR4 group;and pharmaceutically acceptable salts or solvates thereof, in the manufacture of a medicament for use in the inhibition of cathepsin S in a mammal such as man.
In the context of the present specification, unless otherwise indicated, an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituent group may be linear or branched. Aryl groups include phenyl and naphthyl. Heteroaryl groups include 5- or 6-membered, 5,6- or 6,6-fused heterocyclic rings containing one or more heteroatoms selected from N, S, O. Examples include pyridine, pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan, thiophene, quinoline, isoquinoline, benzimidazole, benzofuran, benzothiophene and indole.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
Preferably X is CH, NHR2, OR2 where R2 is preferably H or C1-6 alkyl.
Preferably R is a group Y(CH2)pR7 where p is 0 or 1 and Y is NR8 where R8 is hydrogen and R7 is substituted phenyl. Preferably R7 is phenyl substituted by halogen, especially chloro. More preferably R7 is phenyl substituted by chloro in the 4-position.
Preferably R1 is a group NR13R14 where R13 and R14 together with the nitrogen atom to which they are attached form a morpholine ring, piperidine or piperazine ring optionally substituted, or R1 is a group NR9R10 where R10 is H or C1-6 alkyl and R9 is C1-6 alkyl which can optionally contain one or more O, S or NR4 groups where R4 is hydrogen or C1-6 alkyl.
The most preferred substituents for R and R1 are those of the examples exemplified herein.
Preferred compounds of the invention include:    4-[(4-Chlorophenyl)amino]-6-(dimethylamino)-1,3,5-triazine-2-carbonitrile,    4-Morpholin-4-yl-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,    4-(7-Azabicyclo[2.2.1]hept-7-yl)-6-[(4-chlorophenyl)amino]-1,3,5-triazine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-pyrrolidin-1-yl-1,3,5-triazine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-piperidin-1-yl-1,3,5-triazine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-(ethylamino)-1,3,5-triazine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-(3-hydroxypyrrolidin-1-yl)-1,3,5-triazine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-[(2-piperidin-1-ylethyl)amino]-1,3,5-triazine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-(4-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile,    4-[(3-Chlorobenzyl)amino]-6-(dimethylamino)-1,3,5-triazine-2-carbonitrile,    4-Morpholin-4-yl-6-[(4-morpholin-4-ylphenyl)amino]-1,3,5-triazine-2-carbonitrile,    4-(2,3-Dihydro-1,4-benzodioxin-6-ylamino)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,    4-Morpholin-4-yl-6-(3-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile,    4-(1,4′-Bipiperidin-1′-yl)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,    4-[4-(1H-Imidazol-1-yl)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,    4-[4-(4-Chlorobenzoyl)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,    4-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]-6-morpholinyl-1,3,5-triazine-2-carbonitrile,    4-Morpholin-4-yl-6-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}-1,3,5-triazine-2-carbonitrile,    1-(4-Cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N,N-diethylpiperidine-3-carboxamide,    4-[4-(2-Methoxyphenyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,    N˜2˜-(4-Cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N˜1˜,N˜1˜-bis{4-[N-(4-cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N-isobutylglycyl]morpholin-3-yl}-N˜2˜-isobutylglycinamide,    4-Morpholin-4-yl-6-[(2-pyridin-3-ylethyl)amino]-1,3,5-triazine-2-carbonitrile,    4-{[2-(2-Furyl)ethyl]amino}-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,    4[(4-Chlorophenyl)amino]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-carbonitrile,    4-Azetidin-1-yl-6-[(4-chlorophenyl)amino]-1,3,5-triazine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,    4-[(4-Methylcyclohexyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,    4-(4-Chlorophenoxy)-6-morpholin-4-ylpyrimidine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-(dimethylamino)pyrimidine-2-carbonitrile,    4-[(1-Methylpiperidin-4-yl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,    4-(Cyclohexylamino)-6-morpholin-4-ylpyrimidine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-pyrrolidin-1-ylpyrimidine-2-carbonitrile,    4-[(6-Chloropyridin-3-yl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,    1-{6-[(4-Chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-L-prolinamide,    4-(4-Aminopiperidin-1-yl)-6-[(4-chlorophenyl)amino]pyrimidine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-(4-pyrrolidin-1-ylpiperidin-1-yl)pyrimidine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-[(3-pyrrolidin-1-ylpropyl)amino]pyrimidine-2-carbonitrile,    tert-Butyl 4-{6-[(4-chlorophenyl)amino]-2-cyanopyrimidin-4-yl}piperazine-1-carboxylate,    4-[(4-Chlorophenyl)amino]-6-(cyclopropylamino)pyrimidine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-piperazin-1-ylpyrimidine-2-carbonitrile,    (2S)-N˜2˜-{6-[(4-Chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-N˜1˜,N˜1˜-bis[4-(N-{6-[(4-chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-L-leucyl)morpholin-3-yl]-L-leucinamide,    5-Chloro-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-5-methoxy-6-piperazin-1-ylpyrimidine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-5-methoxy-6-morpholin-4-ylpyrimidine-2-carbonitrile,    4-[(3S)-3-Aminopyrrolidin-1-yl]-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-{4-[3-(dimethylamino)propyl]piperazin-1-yl}-5-methoxypyrimidine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-6-(dimethylamino)-5-methoxypyrimidine-2-carbonitrile,    4-[(4-Chlorophenyl)amino]-5-methoxy-6-(3-oxopiperazin-1-yl)pyrimidine-2-carbonitrile,    1-{6-[(4-Chlorophenyl)amino]-2-cyano-5-methoxypyrimidin-4-yl}piperidine-3-carboxamide,    4-(4-Aminopiperidin-1-yl)-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile,    5-Amino-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,    5-Amino-4[(4-Chlorophenyl)amino]-6-(ethylamino)pyrimidine-2-carbonitrile,and pharmaceutically acceptable salts thereof.
In a further aspect the invention provides a compound of formula (I) as defined above but where X is CH, NHR2, OR2 where R2 is preferably H or C1-6 alkyl. For the novel compounds of the invention other preferred groups and compounds are those defined above.
The present invention further provides a process for the preparation of a compound of formula (I) which comprises    (i) reaction of a compound of general formula (II)
     wherein L1, L2 and L3 represent a leaving group (e.g. halide, sulphide, sulfoxide or sulphone group), preferably the sulphide is oxidised to a sulphoxide or sulphone group before displacement. An oxidising agent such as a peracid may be used, for example meta-chloroperbenzoic acid in dichloromethane at room temperature.
L1 and L2 may be displaced by R and R1 respectively where R and R1 are defined in formula (I) and L3 may be displaced by a cyanide salt. The sequence of displacement of L1, L2 and L3 may be varied.
When X═CA and A=OR2, SR2 or CHR2R3 compounds of general formula (ID may be formed by treatment of compounds of general formula (III) and (IV) with phosphorous oxychloride at reflux. R19 is preferably C1-6 alkyl or benzyl
    (ii) when X═CA and A=NH2 reaction of a compound of general formula (V) under a hydrogen atmosphere with palladium catalyst at room temperature.
According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a therapeutic agent.
According to a further feature of the present invention there is provided a method for producing inhibition of a cysteine protease in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof
The invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament; and the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of a cysteine protease in a warm blooded animal, such as man. In particular the compounds of the invention are useful in the treatment of inflammation and immune disorders such as asthma, rheumatoid arthritis, COPD, multiple sclerosis, Crohn's disease, Alzheimers and pain, such as neuropathic pain. Preferably the compounds of the invention are used to treat pain, in particular neuropathic pain.
In particular the invention provides the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of Cathepsin S in a warm blooded animal, such as man. In order to use a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in the inhibition of a cysteine protease, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 100 mg and 1 g of the compound of this invention.
In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 1 mgkg−1 to 100 mgkg−1 of the compound, preferably in the range of 5 mgkg−1 to 20 mgkg−1 of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), or a pharmaceutically-acceptable salt thereof (hereafter compound X), for therapeutic or prophylactic use in humans:
(a)Tablet Img/tabletCompound X.100Lactose Ph.Eur.179Croscarmellose sodium12.0Polyvinylpyrrolidone6Magnesium stearate3.0(b)Tablet IImg/tabletCompound X50Lactose Ph.Eur.229Croscarmellose sodium12.0Polyvinylpyrrolidone6Magnesium stearate3.0(c)Tablet IIImg/tabletCompound X1.0Lactose Ph.Eur.92Croscarmellose sodium4.0Polyvinylpyrrolidone2.0Magnesium stearate1.0(d)Capsulemg/capsuleCompound X10Lactose Ph.Eur.389Croscarmellose sodium100Magnesium stearate1.(e)Injection I(50 mg/ml)Compound X5.0% w/vIsotonic aqueous solutionto 100%
Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl β cyclodextrin may be used to aid formulation.
Note
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)–(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
The following examples illustrate the invention.